The Journal of Experimental Medicine
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Published online 22 May 2006 doi:10.1084/jem.20052187
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 6, 1459-1470
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ARTICLE

 Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7–dependent homeostatic proliferation of CD4+ T cells

Shin-ichiro Sawa1, Daisuke Kamimura1,2, Gui-Hua Jin1, Hideyuki Morikawa1, Hokuto Kamon1, Mika Nishihara1, Katsuhiko Ishihara1, Masaaki Murakami1, and Toshio Hirano1,2

1 Laboratory of Developmental Immunology, Graduate School of Frontier Bioscience and Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
2 Laboratory for Cytokine Signaling, Institute of Physical and Chemical Research Center for Allergy and Immunology, Yokohama 230-0045, Japan

CORRESPONDENCE Toshio Hirano: hirano{at}molonc.med.osaka-u.ac.jp

Mice homozygous for the F759 mutation in the gp130 interleukin (IL)-6 receptor subunit have enhanced gp130-mediated signal transducer and activator of transcription (STAT)3 activation and spontaneously developed a lymphocyte-mediated rheumatoid arthritis-like joint disease. Here, we show that the development of the disease is dependent on both major histocompatibility complex (MHC) II–restricted CD4+ T cells and IL-6 family cytokines. In spite of the necessity for CD4+ T cells, the gp130 mutation was only required in nonhemtopoietic cells for the disease. The gp130 mutation resulted in enhanced production of IL-7. Conditional knockout of STAT3 in nonlymphoid cells showed that the enhancement of IL-7 production was dependent on STAT3 activation by IL-6 family cytokines. Homeostatic proliferation of CD4+ T cells was enhanced in gp130 mutant mice and acceleration of homeostatic proliferation enhanced the disease, whereas the inhibition of homeostatic proliferation suppressed the disease. Anti–IL-7 antibody treatment inhibited not only the enhanced homeostatic proliferation, but also the disease in gp130 mutant mice. Thus, our results show that autoimmune disease in gp130 mutant mice is caused by increased homeostatic proliferation of CD4+ T cells, which is due to elevated production of IL-7 by nonhematopoietic cells as a result of IL-6 family cytokine-gp130-STAT3 signaling.

Abbreviations used: HP, homeostatic proliferation; MEF, mouse embryonic fibroblast; RA, rheumatoid arthritis; sLN, surface LN; SPF, specific pathogen-free.


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